RRC ID 3804
Author Takagi Y, Hidaka M, Sanada M, Yoshida H, Sekiguchi M.
Title Different initial steps of apoptosis induced by two types of antineoplastic drugs.
Journal Biochem Pharmacol
Abstract O6-Methylguanine and O6-chloroethylguanine are primary DNA lesions produced by two types of antineoplastic drugs, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, TMZ) and 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), respectively. They can be repaired by O6-methylguanine-DNA methyltransferase, coded by the Mgmt gene. Otherwise, these two types of lesions induce apoptosis in different ways. O6-Chloroethylguanine blocks DNA replication thereby inducing apoptosis. On the other hand, O6-methylguanine does not block DNA replication and the resulting O6-methylguanine-thymine mispair is recognized by mismatch repair-related proteins, including MLH1, thereby inducing apoptosis. Reflecting this, mouse cells lacking both MGMT and MLH1 are resistant to TMZ, but not to ACNU. The translocation of phosphatidylserine in cell membrane as well as a change of mitochondrial transmembrane potentials occurred in an MLH1-dependent manner after treatment with TMZ, but no such MLH1 dependency was observed in the case of ACNU treatment. By using cell lines defective in both APAF-1 and MGMT, it was revealed that the APAF-1 function is required for execution of apoptosis induced by either TMZ or ACNU. There is almost 12h delay in occurrence of apoptosis-related mitochondrial depolarization in TMZ-treated cells in comparison to those of ACNU-treated cells, reflecting the fact that at least one cycle of DNA replication is required to trigger apoptosis in the former case, but not in the latter.
Volume 76(3)
Pages 303-11
Published 2008-8-1
DOI 10.1016/j.bcp.2008.05.008
PII S0006-2952(08)00305-5
PMID 18573489
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / physiology Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Apoptosis / genetics Cell Line DNA Damage* DNA Repair* Dacarbazine / analogs & derivatives* Dacarbazine / chemistry Dacarbazine / pharmacology Fibroblasts / drug effects* Fibroblasts / metabolism Fibroblasts / pathology Humans Membrane Potential, Mitochondrial / drug effects Mice Mice, Knockout MutL Protein Homolog 1 Nimustine / chemistry Nimustine / pharmacology* Nuclear Proteins / genetics Nuclear Proteins / physiology O(6)-Methylguanine-DNA Methyltransferase / genetics O(6)-Methylguanine-DNA Methyltransferase / physiology Phosphatidylserines / metabolism Structure-Activity Relationship Temozolomide
IF 4.96
Times Cited 11
DNA material pSVtsA58 ori (-) (RDB01126)